Thromboembolic disease, i.e., blockage of a blood vessel by a blood clot, affects many adults and can be a cause of death. Most spontaneously developing vascular obstructions are due to the formation of intravascular blood clots, also known as thrombi. Small fragments of a clot, emboli, may detach from the body of the clot and travel through the circulatory system to lodge in distant organs and initiate further clot formation. Heart attack, stroke, renal and pulmonary infarcts are well known consequences of thromboembolic phenomena.
A blood clot is a gelled network of protein molecules within which are trapped circulating blood cells, platelets, and plasma proteins. A major protein component of a clot is fibrin, which forms a relatively insoluble network in the clot. Proteolytic enzymes, particularly fibrinolytic enzymes, have been used to dissolve vascular obstructions, since disruption of the fibrin matrix results in dissolution of the clot. Clots are formed when soluble fibrinogen, which is present in high concentrations in blood, is converted to insoluble fibrin by the action of thrombin. Fibrinolytic enzymes dissolve the fibrin matrix of a clot, and fibrinogenolytic enzymes digest the fibrin precursor fibrinogen.
Intravascular clots may be removed after their appearance by means of enzymes capable of dissolving fibrin (fibrinolytic enzymes); and the probability of clot formation can be reduced by lowering the concentration of circulating fibrinogen, using enzymes that degrade fibrinogen (fibrinogenolytic enzymes).
Plasmin, a naturally-occurring fibrinolytic and fibrinogenolytic enzyme, is relatively unstable in the human circulatory system and, therefore, circulates primarily in its more stable inactive form, plasminogen. The activation of plasminogen to plasmin occurs by cleavage of a single arginyl-valine bond and is catalyzed by plasminogen activators. Urokinase and tissue plasminogen activator activate plasminogen by direct cleavage of the arginyl-valine bond. Streptokinase and staphylokinase are plasminogen activators of bacterial origin that activate plasminogen indirectly by forming a complex with plasminogen; this streptokinase-plasminogen complex behaves as a plasminogen activator that activates other plasminogen molecules by cleaving the arginyl-valine bond.
Thromboembolytic therapies have involved the administration of a plasminogen activator; e.g., the direct intravenous injection of a plasminogen activator alone, the reinjection of a patient's plasma to which a plasminogen activator has been added ex vivo, the injection of plasma protein fractions previously mixed with streptokinase, or the injection of a preparation of porcine plasmin stabilized with added lysine in conjunction with streptokinase.
Fibrinogenolytic therapy aimed at reducing the risk of thrombosis has involved injection of snake venoms, e.g., Angkistrodon rhodostoma, which contain enzymes that degrade fibrinogen.